Elucidating the Mechanisms that link the Shared Epitope, Periodontal Disease and Arthritis

阐明共享表位、牙周病和关节炎之间的联系机制

• 批准号: 9352706
• 负责人: DAVID D. BRAND
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352706
• 关键词: Acute; Address; Adult; Affect; Alleles; Alveolar; Alveolar Bone Loss; Anaerobic Bacteria; Animals; Antibodies; Antigen-Antibody Complex; Arthritis; Autoantibodies; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Automobile Driving; Bacteria; Bacterial Infections; Behavioral; Binding; Blood; Cartilage; Cartilage injury; Cells; Cervical lymph node group; Chronic; Citrulline; Collagen Type II; Collagen-Induced Arthritis; Complement; Country; DR1 gene; Data; Degenerative Disorder; Degenerative polyarthritis; Development; Disease; Engineering; Enzymes; Epitopes; Equilibrium; Exhibits; Frequencies; Generations; Genetic; Gingiva; Goals; HLA-DR1 Antigen; Health; Histocompatibility; Human; Immune response; Immunization; Immunize; Incidence; Income; Infection; Inflammation; Inflammatory; Inflammatory Arthritis; Injury; Joints; Knock-out; Lead; Life Style; Link; Measurable; Measures; Mediating; Modeling; Modification; Morbidity - disease rate; Mus; Oral; Oral Administration; Oral cavity; Organism; Pathogenesis; Pathogenicity; Pathway interactions; Periodontal Diseases; Periodontitis; Phenotype; Play; Population; Porphyromonas gingivalis; Preventive measure; Production; Proteins; Protocols documentation; Regulatory T-Lymphocyte; Reporter; Research Project Grants; Rheumatoid Arthritis; Role; Smoking; Stream; Susceptibility Gene; T-Cell Development; T-Lymphocyte; Testing; Tissues; Tobacco use; Tooth structure; Transgenes; Variant; Vascular Permeabilities; Veterans; Visit; alveolar bone; alveolar destruction; arthropathies; autoimmune arthritis; base; bone; bone loss; citrullinated protein; cortical bone; cytokine; design; experimental study; humanized mouse; incomplete Freund' s adjuvant; oral infection; pathogen; pathogenic bacteria; permissiveness; prevent; programs; response; screening; substantia spongiosa

Periodontal disease (PD) and Rheumatoid Arthritis (RA) have many features in common. PD is a chronic inflammatory disease of the periodontium, the soft and hard tissues supporting the teeth, and is characterized by the destruction of the alveolar bone as a result of the chronic bacterial challenge and a compromised immune response. RA is a chronic inflammatory disease of the diarthrodial joints which results in reduced mobility. Both diseases exhibit a strong genetic component, the “shared epitope” (SE) HLA-DRβ1 as well as a lifestyle component such as tobacco use, a lifestyle choice that is prevalent among veterans. We have previously demonstrated that when the shared epitope is added as a transgene to a mouse that is known not to be susceptible to collagen-induced arthritis (CIA), this mouse (B10.M) becomes susceptible to CIA. C57BL/6 (B6) mice have been described as not being susceptible to bone loss or oral colonization with the putative PD pathogen, the gram negative anaerobe Porphyromonas gingivalis in studies of PD. We have engineered a B6 mouse to express a chimeric mouse/human SE as a transgene in the absence of its murine class II (B6.DR1 mouse), and we have begun studies to determine if expression of this HLA-DRβ1 transgene can provide the B6 mouse with the appropriate set of susceptibility genes necessary for colonization with P. gingivalis and for all the pathways that lead to bone destruction. The overarching goal of this program of study is to directly address the mechanistic basis behind the association between periodontitis and the development of arthritis. We hypothesize that periodontitis in the context of permissive tissue types (such as those bearing the SE) will provide the necessary pPAD enzymes to promote host protein citrulline modifications that drive T cell development and subsequent ACPA production. We further hypothesize that ACPAs form immune complexes that enhance vascular permeability and allow binding of any number of joint specific antibodies to the cartilage where innate mechanisms such as complement and FcR binding to propagate arthritis. This study is significant because it has very important implications for veterans bearing the shared epitope. Should our hypothesis prove correct, it will suggest that aggressive preventative measures including a more pro-active periodontal screening with an enhanced frequency of visits may be necessary to prevent arthritis in veterans bearing any allelic variation of the shared epitope. This might also include arthritis that develops following acute injury to the joint. Our preliminary data demonstrate 1) that we can establish an Pg oral infection model in the humanized B6.DR1 mice and that the bacteria are present for a prolong period in the oral cavity, and can be detected in the blood stream, 2) that infection of the oral cavity induces an immune response that can be detected by the presence of ACPA, the generation of Th17 cells, and the induction of several proinflammatory cytokines, 3) that the ACPA response is dependent on the expression of the HLA-DR1 molecule, 4) that Pg infection leads to significant bone loss both in periodontal bones as well as peri- articular bones, and 5) Pg infection induces the development of autoimmune arthritis in mice that have an established autoimmune response but otherwise lack overt signs of disease. Collectively, these data provide critical evidence in support of our primary hypothesis, and the specific aims we propose to use to test this hypothesis.

牙周病(PD)和类风湿性关节炎(RA)有许多共同特征。帕金森病是一种慢性疾病 在牙周组织的fl炎症性疾病中，支持牙齿的软硬组织，是 以牙槽骨的破坏为特征的，这是由于慢性细菌感染和 免疫反应受损。类风湿关节炎(RA)是一种慢性fl炎症性腹泻关节疾病， 导致机动性降低。这两种疾病都表现出强烈的遗传成分，即“共同表位”(SE) HLA-DRβ1以及吸烟等生活方式成分，这是一种普遍的生活方式选择 在退伍军人中。我们之前已经证明，当共享表位作为转基因添加时 对于一只已知不容易患胶原性关节炎(CIA)的小鼠，这只小鼠(B10.M) 变得容易受到中情局的影响。C57BL/6(B6)小鼠被描述为对骨骼不敏感 疑似帕金森病病原体革兰氏阴性厌氧菌卟啉单胞菌缺失或口腔定植 牙周炎在帕金森病研究中的作用。我们已经设计了一只B6小鼠，将嵌合的鼠/人SE表达为 在缺乏其小鼠II类(B6.DR1小鼠)的情况下转基因，我们已经开始研究以确定 如果这种HLADRβ1转基因基因的表达能够为B6小鼠提供适当的一套 牙龈假单胞菌定植和所有通向骨骼的途径所必需的易感基因 毁灭。 这项研究计划的首要目标是直接解决 牙周炎与关节炎发生的关系。我们假设牙周炎在 许可组织类型(如携带SE的组织)的上下文将提供必要的PPAD 酶促进宿主蛋白瓜氨酸Modifi阳离子驱动T细胞发育和随后 ACPA制作。我们进一步假设ACPA形成增强血管的免疫复合体 渗透性和允许任何数量的关节特异性fi-c抗体与软骨结合 补体和FCR结合等机制可促进关节炎的传播。 这项研究意义重大，因为它对退伍军人肩负着共同的责任具有非常重要的意义 表位。如果我们的假设被证明是正确的，它将表明激进的预防措施 包括更积极的牙周筛查和增加就诊频率可能是必要的 以预防携带共享表位的任何等位变异的退伍军人的关节炎。这还可能包括 关节急性损伤后发生的关节炎。 我们的初步数据表明：1)我们可以在人性化的人群中建立PG口腔感染模型 B6.DR1小鼠和细菌在口腔中存在较长时间，并可 在血流中检测到，2)口腔感染引起的免疫反应可以是 通过ACPA的存在，Th17细胞的产生和几个 Proinfl炎性细胞因子，3)ACPA反应依赖于HLADR1的表达 分子，4)PG感染导致牙周骨和周围骨均有明显的骨丢失(ficn)。 关节骨，5)PG感染诱导小鼠自身免疫性关节炎的发展 已建立的自身免疫反应，但在其他方面缺乏明显的疾病迹象。总的来说，这些数据 提供关键证据来支持我们的主要假设，以及我们建议使用的特定fic#目标。 来检验这一假设。